Malaria is the most important parasitic disease in tropical and subtropical regions, and approximately half of the global population lives at risk of this parasitic disease (1). Malaria is a disease caused by parasites of the genus Plasmodium spp. Five Plasmodium species are known to cause malaria in humans, namely Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Malaria mainly caused by P. falciparum and P. vivax is a major public health problem in Asia and Africa. It has been recognized that P. falciparum is the type of malaria that is most likely to result in severe infections and may lead to death. Unlike P. falciparum, P. vivax malaria causes chronic infection owing to a latent liver stage. The increasing resistance and severe side effects to currently available drugs have become important problems for malaria control in most parts of the world (FIG. 1). Accordingly, the development of new antimalarial drugs is an urgent need. Recently, the concept of hybrid drugs has emerged as a new approach in the design of novel antimalarial agents. However, none of the synthesized hybrid compounds have reached clinical application yet (2-6). In general, hybrid molecules are defined as chemical entities with two or more structural domains having different biological functions and dual activity (FIG. 2), indicating that a hybrid molecule acts as two different pharmacophores.
Pyrimethamine is known as an effective antifolate drug against Plasmodium dihydrofolate reductase (DHFR), an essential enzyme in the folate biosynthetic pathway of parasites (7). Several research efforts have been carried out in the syntheses of new antifolate compounds in order to develop effective compounds against resistant malarial strains.
This invention describes the syntheses of antifolate antimalarials which have dual binding modes as disclosed in the disclosure of invention section.